U.S. patent application number 12/551413 was filed with the patent office on 2010-01-07 for system and method of loading and detecting beneficial agent on a prosthesis.
This patent application is currently assigned to Abbott Laboratories. Invention is credited to Keith Cromack, Richard Quint, Peter Tarcha, Donald Verlee.
Application Number | 20100003396 12/551413 |
Document ID | / |
Family ID | 32315003 |
Filed Date | 2010-01-07 |
United States Patent
Application |
20100003396 |
Kind Code |
A1 |
Verlee; Donald ; et
al. |
January 7, 2010 |
System and Method of Loading and Detecting Beneficial Agent on a
Prosthesis
Abstract
An interventional device for delivery of beneficial agent to a
lumen and methods of loading and manufacture of the same, which
include a prosthesis loaded with beneficial agent to provide a
controlled dosage concentration of beneficial agent to the lumen.
The beneficial agent is loaded onto the prosthesis by a
fluid-dispenser having a dispensing element capable of dispensing
the beneficial agent in discrete droplets, each droplet having a
controlled trajectory. The method of loading beneficial agent
includes dispensing beneficial agent in a raster format and/or an
off-axis format along a dispensing path.
Inventors: |
Verlee; Donald;
(Libertyville, IL) ; Tarcha; Peter; (Lake Villa,
IL) ; Cromack; Keith; (Gurnee, IL) ; Quint;
Richard; (Gurnee, IL) |
Correspondence
Address: |
SQUIRE, SANDERS & DEMPSEY LLP
1 MARITIME PLAZA, SUITE 300
SAN FRANCISCO
CA
94111
US
|
Assignee: |
Abbott Laboratories
|
Family ID: |
32315003 |
Appl. No.: |
12/551413 |
Filed: |
August 31, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11465396 |
Aug 17, 2006 |
7597764 |
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12551413 |
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10703820 |
Nov 7, 2003 |
7208190 |
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11465396 |
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60424574 |
Nov 7, 2002 |
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60424575 |
Nov 7, 2002 |
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60424576 |
Nov 7, 2002 |
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60424577 |
Nov 7, 2002 |
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60424607 |
Nov 7, 2002 |
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Current U.S.
Class: |
427/2.24 ;
118/665 |
Current CPC
Class: |
A61F 2002/067 20130101;
A61F 2002/825 20130101; A61F 2/915 20130101; A61F 2/91 20130101;
A61F 2/958 20130101; A61F 2250/0098 20130101; A61F 2250/0068
20130101; B05C 13/025 20130101; A61P 31/04 20180101; A61F 2002/826
20130101; A61F 2002/065 20130101; A61F 2002/91566 20130101; A61F
2210/0004 20130101; A61F 2002/91575 20130101; B05C 5/0216 20130101;
A61F 2/962 20130101; A61F 2002/91533 20130101; A61F 2250/0067
20130101; A61F 2002/91525 20130101; A61F 2/852 20130101; A61F
2002/91558 20130101; G11B 7/00 20130101; A61P 35/00 20180101 |
Class at
Publication: |
427/2.24 ;
118/665 |
International
Class: |
B05D 5/00 20060101
B05D005/00; B05C 11/00 20060101 B05C011/00 |
Claims
1. A system for loading beneficial agent onto a prosthesis for
delivery within a lumen, the system comprising: a holder for
supporting a prosthesis to be deployed within a lumen; a
fluid-dispenser having a dispensing element capable of dispensing
beneficial agent in discrete droplets, each droplet having a
controlled trajectory, the dispensing element and the holder being
movable relative to each other, said dispensing element being
positioned at a distance sufficient such that the dispensing
element and prosthesis in the holder are separated by a distance
that avoids simultaneous contact of the dispensing element and
prosthesis by a discrete droplet; a driver for creating relative
movement between the dispensing element and the holder; a
controller in communication with the driver to define a dispensing
path for dispensing discrete droplets of beneficial agent with the
controlled trajectory in a raster format, the controller also in
communication with the dispensing element to selectively dispense
beneficial agent from the dispensing element to a predetermined
portion of a prosthesis supported by the holder along the
dispensing path; and a beneficial agent detector in communication
with the controller configured to determine an amount of beneficial
agent loaded on a prosthesis, the beneficial agent detector being
configured to be capable of detecting charge build-up on or current
flow from the prosthesis to determine a corresponding amount of
beneficial agent loaded to the prosthesis.
2. The system of claim 1, further including a position detector to
detect when the dispensing element is aligned with the
predetermined portion of the prosthesis supported by the
holder.
3. The system of claim 1, wherein the holder includes a spindle
made of a superelastic material.
4. The system of claim 1, wherein the controller is programmed with
the predetermined portion of the prosthesis to which beneficial
agent is to be dispensed.
5. The system of claim 1, further comprising an identifiable marker
configured to be loaded onto the prosthesis, wherein said
beneficial agent detector in communication with the controller
configured to determine the amount of beneficial agent loaded on
the prosthesis detects the identifiable marker.
6. The system of claim 1, wherein the controller is configured to
instruct dispensing of the beneficial agent onto the prosthesis
until the loaded amount of beneficial agent matches a predetermined
amount of beneficial agent.
7. The system of claim 1, further comprising a charging electrode
adjacent the fluid dispenser configured to add a charge to the
discrete droplets.
8. A system for loading beneficial agent onto a prosthesis for
delivery within a lumen, the system comprising: a holder for
supporting a prosthesis to be deployed within a lumen; a
fluid-dispenser having a dispensing element capable of dispensing
beneficial agent in discrete droplets, each droplet having a
controlled trajectory, the dispensing element and the holder being
movable relative to each other, said dispensing element being
positioned at a distance sufficient such that the dispensing
element and prosthesis in the holder are separated by a distance
that avoids simultaneous contact of the dispensing element and
prosthesis by a discrete droplet; a driver for creating relative
movement between the dispensing element and the holder; a
controller in communication with the driver to define a dispensing
path for dispensing discrete droplets of beneficial agent with the
controlled trajectory in a raster format, the controller also in
communication with the dispensing element to selectively dispense
beneficial agent from the dispensing element to a predetermined
portion of a prosthesis supported by the holder along the
dispensing path, wherein the controlled trajectory is controlled by
the controller so as to not intersect a central axis of the
prosthesis; and a beneficial agent detector in communication with
the controller configured to determine an amount of beneficial
agent loaded on a prosthesis, the beneficial agent detector being
configured to be capable of detecting the number of discrete
droplets dispensed from the fluid-dispenser onto the prosthesis to
determine a corresponding amount of beneficial agent loaded to the
prosthesis.
9. The system of claim 8, further including a position detector to
detect when the dispensing element is aligned with the
predetermined portion of the prosthesis supported by the
holder.
10. The system of claim 8, wherein the holder includes a spindle
made of a superelastic material.
11. The system of claim 8, wherein the controller is programmed
with the predetermined portion of the prosthesis to which
beneficial agent is to be dispensed.
12. A method for loading beneficial agent onto a prosthesis for
delivery within a lumen, the method comprising: supporting on a
holder a prosthesis to be deployed within a lumen; dispensing from
a dispensing element a beneficial agent in discrete droplets, each
droplet having a controlled trajectory; positioning the dispensing
element at a distance from the holder, the distance sufficient to
avoid simultaneous contact of the dispensing element and prosthesis
by the dispensed discrete droplets; moving the holder and the
dispensing element relative to each other, the movement defining a
dispensing path for the dispensing of the discrete droplets of the
beneficial agent with the controlled trajectory in a raster format;
and determining an amount of the beneficial agent dispensed on the
prosthesis.
13. The method of claim 12, wherein the determining of the amount
of the beneficial agent dispensed on the prosthesis includes
detecting a charge build-up on or current flow from the
prosthesis.
14. The method of claim 12, wherein the determining of the amount
of the beneficial agent dispensed on the prosthesis includes
detecting the number of discrete droplets dispensed from the
dispensing element onto the prosthesis.
15. The method of claim 12, wherein the controlled trajectory does
not intersect a central axis of the prosthesis.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of application Ser. No.
11/465,396 filed Aug. 17, 2006, which is a divisional of
application Ser. No. 10/703,820, filed Nov. 7, 2003, now U.S. Pat.
No. 7,208,190, which claims the benefit of Provisional Application
Nos. 60/424,574; 60/424,575; 60/424,576; 60/424,577; and
60/424,607, each of the provisional applications filed on Nov. 7,
2002. Each of the above-identified applications are incorporated
herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The invention relates to a method and system for loading
beneficial agent onto a prosthesis using a fluid-dispenser having a
dispensing element capable of dispensing beneficial agent in
discrete droplets, each droplet having a controlled trajectory. The
method in particular relates to a method of dispensing beneficial
agent in a raster format and/or an off-axis format along a
dispensing path.
[0004] 2. Description of Related Art
[0005] Percutaneous transluminal coronary angioplasty (PTCA) is a
procedure for treating heart disease. This procedure generally
entails introducing a catheter assembly into the cardiovascular
system of a patient via the brachial or femoral artery, and
advancing the catheter assembly through the coronary vasculature
until a balloon portion thereon is positioned across an occlusive
lesion. Once in position across the lesion, the balloon is inflated
to a predetermined size to radially compress against the
atherosclerotic plaque of the lesion to remodel the vessel wall.
Subsequently, the balloon is deflated to allow the catheter
assembly to be withdrawn from the vasculature.
[0006] While PCTA is widely used, it suffers from two unique
problems. First, the blood vessel may suffer acute occlusion
immediately after or within the initial hours after the dilation
procedure. Such occlusion is referred to as "abrupt closure."
Abrupt closure occurs in approximately five percent of cases in
which PTCA is employed. The primary mechanisms of abrupt closures
are believed to be elastic recoil, arterial dissection and/or
thrombosis. The second problem associated with this procedure is
the re-narrowing of an artery after an initially successful
angioplasty. This re-narrowing is referred to as "restenosis,"
which typically occurs within the first six months after
angioplasty. Restenosis is believed to be due to, among other
things, the proliferation and migration of cellular components from
the arterial wall, as well as through geometric changes in the
arterial wall referred to as "remodeling."
[0007] To reduce occlusion of the artery, and the development of
thrombosis and/or restenosis, an expandable interventional device
or prosthesis, one example of which includes a stent, is implanted
in the lumen to maintain the vascular patency. Additionally, to
better effectuate the treatment of such vascular disease, it is
preferable to load an intraluminal device or prosthesis with one or
more beneficial agents, such as antiproliferatives, for delivery to
a lumen. One commonly applied technique for the local delivery of a
drug is through the use of a polymeric carrier coated onto the
surface of a stent, as disclosed in Berg et al., U.S. Pat. No.
5,464,650, the disclosure of which is incorporated herein by
reference thereto. Such conventional methods and products generally
have been considered satisfactory for their intended purpose.
However, some problems associated with such drug eluting
interventional devices is the variability in drug loading across an
interventional device, as well as the variability in drug
concentration from device to device. Other disadvantages include
the inability to tightly control and maintain drug concentration,
the inability to verify drug distribution or drug loading on any
given device, the inability to vary drug distribution in a
controlled and predetermined manner to effect a more desirable drug
loading profile, the inability to load different, and in particular
incompatible or reactive drugs onto the same surface of a device,
and the difficulty in controlling the local areal density of
beneficial agent that is delivered to the lumen, particularly if
the interventional device is an overlapping or bifurcated device
coated with beneficial agent.
[0008] As evident from the related art, conventional methods of
loading interventional devices with beneficial agents, such as
drugs, often requires coating the entire prosthesis with a polymer
capable of releasing therapeutic drugs, as disclosed in Campbell,
U.S. Pat. No. 5,649,977 and Dinh et al., U.S. Pat. No. 5,591,227,
the disclosures of which are incorporated herein by reference
thereto. Because certain interventional devices may have a varied
surface area along its length, such conventional loading techniques
results in unintentional or undesirable dosage variations.
Additionally, if it is desired to superimpose two or more
conventional-loaded prostheses, such as with nested stents or
bifurcated stents, the total dosage of beneficial agent to the
lumen will exceed the nominal or desired dosage. Another drawback
of the conventional methods of loading interventional devices with
beneficial agents is the lack of selective dosing, such as
providing various beneficial agents or various concentrations of
the same beneficial agent at different locations on a prosthesis to
effect a therapy at specific targeted sites.
[0009] Thus, there remains a need for efficient and economic
methods for controlling the loading of beneficial agent onto a
prosthesis so as to provide an interventional device having a
varied distribution profile of beneficial agent to effect therapy
at targeted locations of the lumen. Additionally, there is a need
for an interventional device capable of providing combination
therapy of two or more beneficial agents loaded on different
surfaces of a prosthesis to effectuate systemic release as well as
release to the wall of the lumen. Further, a need exists for the
loading of incompatible beneficial agents onto the same surface of
a prosthesis. The advantages of the present invention satisfy the
aforementioned needs.
SUMMARY OF THE INVENTION
[0010] The purpose and advantages of the present invention will be
set forth in and will become apparent from the description that
follows, as well as will be learned by practice of the
invention.
[0011] Additionally, advantages of the invention will be realized
and attained by the methods and systems particularly pointed out in
the written description and claims hereof, as well as from the
appended drawings.
[0012] In aspects of the present invention, a system for loading
beneficial agent onto a prosthesis for delivery within a lumen
comprises a holder, a fluid-dispenser, a driver, a controller, and
a beneficial agent detector. The holder is for supporting a
prosthesis to be deployed within a lumen. The fluid-dispenser has a
dispensing element capable of dispensing beneficial agent in
discrete droplets, each droplet having a controlled trajectory, the
dispensing element and the holder being movable relative to each
other, said dispensing element being positioned at a distance
sufficient such that the dispensing element and prosthesis in the
holder are separated by a distance that avoids simultaneous contact
of the dispensing element and prosthesis by a discrete droplet. The
driver is for creating relative movement between the dispensing
element and the holder. The controller is in communication with the
driver to define a dispensing path for dispensing discrete droplets
of beneficial agent with the controlled trajectory in a raster
format, the controller is also in communication with the dispensing
element to selectively dispense beneficial agent from the
dispensing element to a predetermined portion of a prosthesis
supported by the holder along the dispensing path. The beneficial
agent detector is in communication with the controller configured
to determine an amount of beneficial agent loaded on a prosthesis,
the beneficial agent detector being configured to be capable of
detecting charge build-up on or current flow from the prosthesis to
determine a corresponding amount of beneficial agent loaded to the
prosthesis.
[0013] In other aspects, the controlled trajectory is controlled by
the controller so as to not intersect a central axis of the
prosthesis.
[0014] In other aspects, the beneficial agent detector is
configured to be capable of detecting the number of discrete
droplets dispensed from the fluid-dispenser onto the prosthesis to
determine a corresponding amount of beneficial agent loaded to the
prosthesis.
[0015] In aspects of the present invention, a method for loading
beneficial agent onto a prosthesis for delivery within a lumen
comprising supporting on a holder a prosthesis to be deployed
within a lumen. The method further comprises dispensing from a
dispensing element a beneficial agent in discrete droplets, each
droplet having a controlled trajectory. The method further
comprises positioning the dispensing element at a distance from the
holder, the distance sufficient to avoid simultaneous contact of
the dispensing element and prosthesis by the dispensed discrete
droplets. The method further comprises moving the holder and the
dispensing element relative to each other, the movement defining a
dispensing path for the dispensing of the discrete droplets of the
beneficial agent with the controlled trajectory in a raster format.
The method further comprises determining an amount of the
beneficial agent dispensed on the prosthesis.
[0016] In further aspects, the determining of the amount of the
beneficial agent dispensed on the prosthesis includes detecting a
charge build-up on or current flow from the prosthesis.
[0017] In further aspects, the determining of the amount of the
beneficial agent dispensed on the prosthesis includes detecting the
number of discrete droplets dispensed from the dispensing element
onto the prosthesis.
[0018] In further aspects, the controlled trajectory does not
intersect a central axis of the prosthesis.
[0019] It is to be understood that both the foregoing general
description and the following detailed description are exemplary
and are intended to provide further explanation of the invention
claimed.
[0020] The accompanying Figures, which are incorporated in and
constitute part of this specification, are included to illustrate
and provide a further understanding of the method and system of the
invention. Together with the description, the Figures serve to
explain the principles of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] FIGS. 1a-1c are schematic representations of a prosthesis
loaded with beneficial agent having a first portion and a second
portion having different local areal densities of beneficial agent
in accordance with the present invention, and graphs depicting
corresponding areal density.
[0022] FIG. 2 is a schematic representation of a first prosthesis
and a second prosthesis configured to define a nested
interventional device, each at least partially loaded with
beneficial agent in accordance with the present invention.
[0023] FIG. 3 is a schematic representation of the first prosthesis
and second prosthesis of FIG. 2, deployed in overlapping
relationship to provide a controlled local areal density across the
length of the interventional device.
[0024] FIG. 4 is a schematic representation of a first prosthesis
and second prosthesis configured to define a bifurcated
interventional device, each at least partially loaded with
beneficial agent in accordance with the present invention.
[0025] FIG. 5 is a schematic representation of the first prosthesis
and second prosthesis of FIG. 4, deployed in an overlapping
relationship to provide a bifurcated interventional device having a
controlled local areal density across a length of the
interventional device.
[0026] FIG. 6 is a schematic representation of an interventional
device, and FIG. 6a is a detail schematic depicting a raster format
for loading beneficial agent thereon.
[0027] FIG. 7 is a schematic representation of an embodiment of the
system of the present invention.
[0028] FIGS. 8a-8d are schematic representations of an "off-axis"
dispensing method at various cross-sections of the device of FIG.
6.
[0029] FIG. 9 is a schematic representation of another embodiment
of the system of the present invention.
[0030] FIG. 10 is a schematic representation of discrete droplets
loaded in an overlapping manner.
[0031] FIG. 11 is a schematic representation of a method of loading
beneficial agent on an inner surface of an interventional
device.
[0032] FIG. 12 is a schematic representation of the cross-section
of the structural element of a prosthesis having a cavity
therein.
[0033] FIG. 13 is a schematic representation of the holding tool
assembly of the system of the invention, FIG. 13a is a detail
schematic depicting the holding tool assembly including the
spindle.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0034] Reference will now be made in detail to the present
preferred embodiments of the method and system for loading
beneficial agent onto a prosthesis, and the interventional devices
loaded with beneficial agent. Wherever possible, the same reference
characters will be used throughout the drawings to refer to the
same or like parts.
[0035] In accordance with the present invention, an interventional
device is provided for delivery of beneficial agent within a lumen.
Particularly, the present invention is suited for providing an
interventional device having a controlled areal density of
beneficial agent for the treatment and prevention of vascular or
other intraluminal diseases. Generally, "controlled areal density"
is understood to mean a known or predetermined amount of beneficial
agent, either by weight or volume, over a unit surface area of the
interventional device.
[0036] As used herein "interventional device" refers broadly to any
device suitable for intraluminal delivery or implantation. For
purposes of illustration and not limitation, examples of such
interventional devices include stents, grafts, stent-grafts,
filters, and the like. As is known in the art, such devices may
comprise one or more prostheses, each having a first
cross-sectional dimension or profile for the purpose of delivery
and a second cross-sectional dimension or profile after deployment.
Each prosthesis may be deployed by known mechanical techniques such
as balloon expansion deployment techniques, or by electrical or
thermal actuation, or self-expansion deployment techniques, as well
known in the art. Examples of such for purpose of illustration
include U.S. Pat. No. 4,733,665 to Palmaz; U.S. Pat. No. 6,106,548
to Roubin et al.; U.S. Pat. No. 4,580,568 to Gianturco; U.S. Pat.
No. 5,755,771 to Penn et al.; and U.S. Pat. No. 6,033,434 to
Borghi, all of which are incorporated herein by reference.
[0037] For purposes of explanation and illustration, and not
limitation, an exemplary embodiment of the interventional device in
accordance with the invention is shown schematically in FIG. 1a. In
accordance with one aspect of the invention, as shown schematically
in FIG. 1, the interventional device generally includes a
prosthesis 10 loaded with beneficial agent to provide a local areal
density of beneficial agent across a length of the interventional
device. Particularly, as embodied herein the prosthesis may be a
stent, a graft, a stent-graft, a filter, or the like, as previously
noted, for intravascular or coronary delivery and/or implantation.
However, the prosthesis may be any type of intraluminal member
capable of being loaded with beneficial agent.
[0038] The prosthesis can be in an expanded or unexpanded state
during the loading of beneficial agent. The underlying structure of
the prosthesis can be virtually any structural design and the
prosthesis can be composed any suitable material such as, but not
limited to, stainless steel, "MP35N," "MP20N," elastinite
(Nitinol), tantalum, nickel-titanium alloy, platinum-iridium alloy,
gold, magnesium, polymer, ceramic, tissue, or combinations thereof
"MP35N" and "MP20N" are understood to be trade names for alloys of
cobalt, nickel, chromium and molybdenum available from Standard
Press Steel Co., Jenkintown, Pa. "MP35N" consists of 35% cobalt,
35% nickel, 20% chromium, and 10% molybdenum. "MP20N" consists of
50% cobalt, 20% nickel, 20% chromium and 10% molybdenum. The
prosthesis can be made from bioabsorbable or biostable polymers. In
some embodiments, the surface of the prosthesis can include one or
more reservoirs or cavities formed therein, as described further
below.
[0039] The prosthesis can be fabricated utilizing any number of
methods known in the art. For example, the prosthesis can be
fabricated from a hollow or formed tube that is machined using
lasers, electric discharge milling, chemical etching or other known
techniques. Alternatively, the prosthesis can be fabricated from a
sheet that is rolled into a tubular member, or formed of a wire or
filament construction as known in the art.
[0040] As noted above, the prosthesis is at least partially loaded
with beneficial agent (10a, 10b, 10c). "Beneficial agent" as used
herein, refers to any compound, mixture of compounds, or
composition of matter consisting of a compound, which produces a
beneficial or useful result. The beneficial agent can be a polymer,
a marker, such as a radiopaque dye or particles, or can be a drug,
including pharmaceutical and therapeutic agents, or an agent
including inorganic or organic drugs without limitation. The agent
or drug can be in various forms such as uncharged molecules,
components of molecular complexes, pharmacologically-acceptable
salts such as hydrochloride, hydrobromide, sulfate, laurate,
palmitate, phosphate, nitrate, borate, acetate, maleate, tartrate,
oleate, and salicylate.
[0041] An agent or drug that is water insoluble can be used in a
form that is a water-soluble derivative thereof to effectively
serve as a solute, and on its release from the device, is converted
by enzymes, hydrolyzed by body pH, or metabolic processes to a
biologically active form. Additionally, the agents or drug
formulations can have various known forms such as solutions,
dispersions, pastes, particles, granules, emulsions, suspensions
and powders. The drug or agent may or may not be mixed with polymer
or a solvent as desired.
[0042] For purposes of illustration and not limitation, the drug or
agent can include antithrombotics, anticoagulants, antiplatelet
agents, thrombolytics, antiproliferatives, anti-inflammatories,
agents that inhibit hyperplasia, inhibitors of smooth muscle
proliferation, antibiotics, growth factor inhibitors, or cell
adhesion inhibitors. Other drugs or agents include but are not
limited to antineoplastics, antimitotics, antifibrins,
antioxidants, agents that promote endothelial cell recovery,
antiallergic substances, radiopaque agents, viral vectors,
antisense compounds, oligionucleotides, cell permeation enhancers,
angiogenesis agents, and combinations thereof.
[0043] Examples of such antithrombotics, anticoagulants,
antiplatelet agents, and thrombolytics include sodium heparin, low
molecular weight heparins, heparinoids, hirudin, argatroban,
forskolin, vapriprost, prostacyclin and prostacylin analogues,
dextran, D-phe-pro-arg-chloromethylketone (synthetic antithrombin),
dipyridamole, glycoprotein IIb/IIIa (platelet membrane receptor
antagonist antibody), recombinant hirudin, and thrombin inhibitors
such as ANGIOMAX.TM., from Biogen, Inc., Cambridge, Mass.; and
thrombolytic agents, such as urokinase, e.g., ABBOKINASE.TM. from
Abbott Laboratories Inc., North Chicago, Ill., recombinant
urokinase and pro-urokinase from Abbott Laboratories Inc., tissue
plasminogen activator (ALTEPLASE.TM. from Genentech, South San
Francisco, Calif. and tenecteplase (TNK-tPA).
[0044] Examples of such cytostatic or antiproliferative agents
include rapamycin and its analogs such as everolimus, ABT-578,
i.e.,
3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,2-
1,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(-
1S,3R,4R)-3-methoxy-4-tetrazol-1-yl)cyclohexyl]-1-methylethyl]-10,21-dimet-
hoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyc-
lohentriacontine-1,5,11,28,29(4H,6H,3 1H)-pentone;23,27-Epoxy-3H
pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pento-
ne, which is disclosed in U.S. Pat. No. 6,015,815, U.S. Pat. No.
6,329,386, US Publication 2003/129215, filed on Sep. 6, 2002, and
US Publication 2002/123505, filed Sep. 10, 2001, the disclosures of
which are each incorporated herein by reference thereto, tacrolimus
and pimecrolimus, angiopeptin, angiotensin converting enzyme
inhibitors such as captopril, e.g, CAPOTEN.RTM. and CAPOZIDE.RTM.
from Bristol-Myers Squibb Co., Stamford, Conn., cilazapril or
lisinopril, e.g., PRINIVIL.RTM. and PRINZIDE.RTM. from Merck &
Co., Inc., Whitehouse Station, N.J.; calcium channel blockers such
as nifedipine, amlodipine, cilnidipine, lercanidipine, benidipinie,
trifluperazine, diltiazem and verapamil, fibroblast growth factor
antagonists, fish oil (omega 3-fatty acid), histamine antagonists,
lovastatin, e.g. MEVACOR.RTM. from Merck & Co., Inc.,
Whitehouse Station, N.J. In addition, topoisomerase inhibitors such
as etoposide and topotecan, as well as antiestrogens such as
tamoxifen may be used.
[0045] Examples of such anti-inflammatories include colchicine and
glucocorticoids such as betamethasone, cortisone, dexamethasone,
budesonide, prednisolone, methylprednisolone and hydrocortisone.
Non-steroidal anti-inflammatory agents include flurbiprofen,
ibuprofen, ketoprofen, fenoprofen, naproxen, diclofenac,
diflunisal, acetominophen, indomethacin, sulindac, etodolac,
diclofenac, ketorolac, meclofenamic acid, piroxicam and
phenylbutazone.
[0046] Examples of such antineoplastics include alkylating agents
such as altretamine, bendamucine, carboplatin, carmustine,
cisplatin, cyclophosphamide, fotemustine, ifosfamide, lomustine,
nimustine, prednimustine, and treosulfin, antimitotics such as
vincristine, vinblastine, paclitaxel, e.g., TAXOL.RTM. by
Bristol-Myers Squibb Co., Stamford, Conn., docetaxel, e.g.,
TAXOTERE.RTM. from Aventis S.A., Frankfort, Germany,
antimetabolites such as methotrexate, mercaptopurine, pentostatin,
trimetrexate, gemcitabine, azathioprine, and fluorouracil, and
antibiotics such as doxorubicin hydrochloride, e.g.,
ADRIAMYCIN.RTM. from Pharmacia & Upjohn, Peapack, N.J., and
mitomycin, e.g., MUTAMYCIN.RTM. from Bristol-Myers Squibb Co.,
Stamford, Conn., agents that promote endothelial cell recovery such
as Estradiol.
[0047] Additional drugs which may be utilized in this application
include dexamethasone; fenofibrate; inhibitors of tyrosine kinase
such as RPR-101511A; PPAR-alpha agonists such as TRICOR.TM.
formulation from Abbott Laboratories Inc., North Chicago, Ill.;
endothelin receptor antagonists such as ABT-627 having general
formula C.sub.29H.sub.38N.sub.2O.sub.6.ClH, and the following
structural formula
##STR00001##
from Abbott Laboratories Inc., North Chicago, Ill., as disclosed in
U.S. Pat. No. 5,767,144, the disclosure of which is incorporated
herein by reference; matrix metalloproteinase inhibitors such as
ABT-518
{[S-(R*,R*)]-N-[1-(2,2-dimethyl-1,3-dioxol-4-yl)-2-[[4-[4-(trifluoro-meth-
oxy)-phenoxy]phenyl]sulfonyl]ethyl]-N-hydroxyformamide}, having
general formula C.sub.21H.sub.22F.sub.3NO.sub.8S and having the
following structural formula
##STR00002##
from Abbott Laboratories Inc., North Chicago, Ill., which is
disclosed in U.S. Pat. No. 6,235,786, the disclosure of which is
incorporated herein by reference; ABT 620
{1-Methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide},
which is disclosed in U.S. Pat. No. 6,521,658, the disclosure of
which is incorporated herein by reference; antiallergic agents such
as permirolast potassium nitroprusside, phosphodiesterase
inhibitors, prostaglandin inhibitors, suramin, serotonin blockers,
steroids, thioprotease inhibitors, triazolopyrimidine, and nitric
oxide.
[0048] While the foregoing beneficial agents are known for their
preventive and treatment properties, the substances or agents are
provided by way of example and are not meant to be limiting.
Further, other beneficial agents that are currently available or
may be developed are equally applicable for use with the present
invention.
[0049] If desired or necessary, the beneficial agent can include a
binder to carry, load, or allow sustained release of an agent, such
as but not limited to a suitable polymer or similar carrier. The
term "polymer" is intended to include a product of a polymerization
reaction inclusive of homopolymers, copolymers, terpolymers, etc.,
whether natural or synthetic, including random, alternating, block,
graft, branched, cross-linked, blends, compositions of blends and
variations thereof. The polymer may be in true solution, saturated,
or suspended as particles or supersaturated in the beneficial
agent. The polymer can be biocompatible, or biodegradable.
[0050] For purpose of illustration and not limitation, the
polymeric material include phosphorylcholine linked macromolecules,
such as a macromolecule containing pendant phosphorylcholine groups
such as poly(MPC.sub.w:LMA.sub.x:HPMA.sub.y:TSMA.sub.z), where MPC
is 2-methacryoyloxyethylphosphorylcholine, LMA is lauryl
methacrylate, HPMA is hydroxypropyl methacrylate and TSMA is
trimethoxysilylpropyl methacrylate, polycaprolactone,
poly-D,L-lactic acid, poly-L-lactic acid,
poly(lactide-co-glycolide), poly(hydroxybutyrate),
poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,
polyanhydride, poly(glycolic acid), poly(glycolic
acid-co-trimethylene carbonate), polyphosphoester, polyphosphoester
urethane, poly(amino acids), cyanoacrylates, poly(trimethylene
carbonate), poly(iminocarbonate), polyalkylene oxalates,
polyphosphazenes, polyiminocarbonates, and aliphatic
polycarbonates, fibrin, fibrinogen, cellulose, starch, collagen,
PARYLENE.RTM., PARYLAST.RTM., polyurethane including polycarbonate
urethanes, polyethylene, polyethylene terapthalate, ethylene vinyl
acetate, ethylene vinyl alcohol, silicone including polysiloxanes
and substituted polysiloxanes, polyethylene oxide, polybutylene
terepthalate-co-PEG, PCL-co-PEG, PLA-co-PEG, polyacrylates,
polyvinyl pyrrolidone, polyacrylamide, and combinations thereof.
Non-limiting examples of other suitable polymers include
thermoplastic elastomers in general, polyolefin clastomers, EPDM
rubbers and polyamide elastomers, and biostable plastic material
such as acrylic polymers, and its derivatives, nylon, polyesters
and epoxies. Preferably, the polymer contains pendant phosphoryl
groups as disclosed in U.S. Pat. Nos. 5,705,583 and 6,090,901 to
Bowers et al. and U.S. Pat. No. 6,083,257 to Taylor et al., which
are all incorporated herein by reference.
[0051] The beneficial agent can include a solvent. The solvent can
be any single solvent or a combination of solvents. For purpose of
illustration and not limitation, examples of suitable solvents
include water, aliphatic hydrocarbons, aromatic hydrocarbons,
alcohols, ketones, dimethyl sulfoxide, tetrahydrofuran,
dihydrofuran, dimethylacetamide, acetates, and combinations
thereof. Preferably, the solvent is ethanol. More preferably, the
solvent is isobutanol. Additionally, in another aspect of the
invention, multiple beneficial agents are dissolved or dispersed in
the same solvent. For purpose of illustration and not for
limitation, dexamethasone, estradiol, and paclitaxel are dissolved
in isobutanol. Alternatively, dexamethasone, estradiol, and
paclitaxel are dissolved in ethanol. In yet another example,
dexamethasone, estradiol, and ABT-578, i.e., the rapamycin analog,
3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21
S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexad-
ecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-3-methoxy-4-tetrazol-1-yl)cy-
clohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27--
epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31-
H)-pentone;
23,27-Epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4-
H,6H,3H)-pentone, are dissolved together in one solvent.
Preferably, the solvent is ethanol. More preferably, the solvent is
isobutanol.
[0052] Additionally, the beneficial agent includes any of the
aforementioned drugs, agents, polymers, and solvents either alone
or in combination.
[0053] A number of methods can be used to load the beneficial agent
onto the surface of the prosthesis to provide for a controlled
local areal density of beneficial agent if performed appropriately.
For example, the prosthesis can be constructed to include pores or
reservoirs which are impregnated or filled with beneficial agent or
multiple beneficial agents. The pores can be sized or spaced apart
to correspond to or limit the amount of beneficial agent contained
therein in accordance with the desired local areal density pattern
along the length of the interventional device, wherein larger pores
or more dense spacing would be provided in such portions intended
to have a greater local areal density. Alternatively, uniform pores
sizes can be provided but the amount of beneficial agent loaded
therein is limited accordingly. Additionally, if desired, a
membrane of biocompatible material can then be applied over the
pores or reservoirs for sustained or controlled release of the
beneficial agent from the pores or reservoirs.
[0054] According to some of the embodiments, the beneficial agent
can be loaded directly onto the prosthesis or alternatively, the
beneficial agent is loaded onto a base material layer that is
applied to a surface of the prosthesis. For example and not
limitation, a base coating, such as a binder or suitable polymer,
is applied to a selected surface of the prosthesis such that a
desired pattern is formed on the prosthesis surface. Beneficial
agent is then applied directly to the pattern of the base
material.
[0055] In one aspect of the invention, the desired pattern
corresponds to the desired controlled local areal density. For
example, a greater amount of base material layer is applied to
portions of the interventional device intended to have a greater
local areal density of beneficial agent, and a lesser amount of
base material is applied to portions of the interventional device
intended to have a lower local areal density of beneficial
agent.
[0056] Alternatively, a suitable base coating capable of retaining
beneficial agent therein can be applied uniformly over the surface
of the prosthesis, and then selected portions of the base coating
can be loaded with the beneficial agent in accordance with the
invention. A greater amount of beneficial agent would be loaded
over a unit surface area of the base coating intended to have a
greater local areal density and a lower amount of beneficial agent
would be loaded over a unit surface area intended to have a lower
local areal density.
[0057] In yet another embodiment of the present invention, the
beneficial agent can be applied directly to the surface of the
prosthesis. Generally a binder or similar component can be required
to ensure sufficient adhesion. For example, this coating technique
can include admixing the beneficial agent with a suitable binder or
polymer to form a coating mixture, which is then coated onto the
surface of the prosthesis. The coating mixture is prepared in
higher or lower concentrations of beneficial agent as desired, and
then applied to selected portions of the prosthesis
appropriately.
[0058] In any of the embodiments disclosed herein, a porous or
biodegradable membrane or layer made of biocompatible material can
be coated over the beneficial agent for sustained release thereof,
if desired.
[0059] Conventional coating techniques can be utilized to coat the
beneficial agent onto the surface of the prosthesis such as
spraying, dipping or sputtering and still provide the desired
effect if performed appropriately. With such techniques, it may be
desirable or necessary to use known masking or extraction
techniques to control the location and amount in which beneficial
agent is loaded. Prior to coating the prosthesis with beneficial
agent, optical machine vision inspection of the prosthesis
preferably is utilized to ensure that no mechanical defects exist.
Defective prostheses thus can be rejected before wasting beneficial
agent, some of which may be very costly.
[0060] In accordance with one aspect of the invention, however, the
beneficial agent is "printed" onto the surface of the prosthesis by
a fluid-dispenser having a dispensing element capable of dispensing
beneficial agent in discrete droplets, wherein each droplet has a
controlled trajectory. If desired, printing can be combined with
conventional coating techniques such as spraying or dipping.
[0061] "Fluid-dispenser," as used herein, refers broadly to any
device having a dispensing element capable of dispensing fluid in
discrete droplets wherein each droplet has a controlled trajectory.
For purposes of illustration and not limitation, examples of such
fluid-dispensers include fluid-jetting and similar fluid dispensing
technology devices such as a drop-on-demand fluid printer and a
charge-and-deflect fluid printer. However, other fluid-dispensers
capable of forming a fluid jet or capable of dispensing discrete
droplets having a controlled trajectory are within the scope of the
present invention. In a preferred embodiment, the fluid-dispenser
is a fluid-jet print head. Such equipment is available from
MicroFab Technologies of Plano, Tex.
[0062] Fluid-jetting and similar technology provides numerous
advantages not available with conventional loading techniques. For
example, fluid jetting technology can be used to deposit materials,
such as chemical reagents, in controlled volumes onto a substrate
at a controlled location, as disclosed in U.S. Pat. No. 4,877,745
to Hayes et al., incorporated herein by reference.
[0063] Fluid jetting can also be used to deposit materials in a
reproducible way. Fluid-jet based deposition of materials is data
driven, non-contact, and requires no tooling. The "printing"
information can be created directly from CAD information and stored
digitally in software or hardware. Thus, no masks or screens are
required. As an additive process with no chemical waste,
fluid-jetting is environmentally friendly. Other advantages include
the efficiency of fluid jet printing technology. For example,
fluid-jetting can dispense spheres of fluid with diameters of
15-200 um at rates of 1-25,000 per second for single droplets on
demand, and up to 1 MHz for continuous droplets. See Cooley et al.,
"Applications of Ink-Jet Printing Technology to BioMEMS and
Microfluidic Systems," Proc. SPIE Conf. on Microfluidics, (October
2001), incorporated herein by reference.
[0064] In accordance with one aspect of the invention, a method of
loading beneficial agent onto a prosthesis for delivery within a
lumen is disclosed. The method comprises the steps of providing a
prosthesis, beneficial agent to be delivered from the prosthesis,
and a fluid-dispenser having a dispensing element capable of
dispensing the beneficial agent in discrete droplets, wherein each
droplet has a controlled trajectory. The method further includes
creating relative movement between the dispensing element and the
prosthesis to define a dispensing path and selectively dispensing
the beneficial agent in a raster format to a predetermined portion
of the prosthesis along the dispensing path. In particular, the
beneficial agent is selectively dispensed from the dispensing
element to a predetermined portion of the prosthesis in a raster
format along a dispensing path. As used herein "raster format"
refers to a continuous or non-continuous dispensing pattern of
droplets of beneficial agent dispensed at specific intervals. The
relative motion of the dispensing element and the prosthesis to be
loaded with beneficial agent creates a dispensing path which
includes, for example and as shown in FIG. 6a, a sequential series
of linear parallel passes 154 that traverse back and forth along
one axis of the prosthesis. The relative motion is continued in a
linear manner between forward and backward or right to left and
left to right or upward and downward, depending on the frame of
reference. A traversal or a pass 154 is completed when the relative
motion reverses direction. That is, relative motion continues past
the prosthesis, and then decelerates, stops, reverses direction and
accelerates to a constant velocity. After each pass, the position
of the dispensing element 150 or prosthesis 10 relative to the
dispensing element preferably is changed or incremented such that
additional droplets do not impact in the same location during the
subsequent pass, although a certain degree of overlap may be
permitted. For example, as the dispensing element dispenses the
beneficial agent along the prosthesis, a fluid dispensing width "w"
is defined. The dispensing path defined by the relative movement
between the dispensing element and the prosthesis can include a
series of parallel passes wherein each parallel pass has a path
width no greater than the fluid dispensing width defined by the
dispensing element, although a greater path width can be defined if
desired.
[0065] Alternatively, the dispensing path created by the relative
motion of the dispensing element 150 and the prosthesis 10 can
include a single continuous helix that wraps continuously around
the prosthesis tubular body and along the length of the prosthesis.
FIG. 10 schematically depicts such a helical path. In this manner,
selectively fluid dispensing in a raster format similar to that of
the linear paths previously described can be performed using a
helical path if desired. In a preferred embodiment, the direction
of travel of relative motion consists of continuously rotating, for
example, the prosthesis 10 to be loaded and then incrementally
advancing the dispensing element axially along the prosthesis. Both
axial and radial motion preferably begin before the prosthesis 10
is aligned with the dispensing element 150 to receive droplets, so
as to enable acceleration of both axes to a constant velocity, and
continues beyond the prosthesis where both movements may
decelerate, and stop. After each rotation, the position of the
dispensing element 150 or of the prosthesis 10 relative to the
dispensing element is moved or incremented axially such that
additional droplets of beneficial agent preferably do not impact in
the same location, Any degree of overlap may be permitted to
achieve the desired areal density of beneficial agent.
[0066] For purpose of illustration of this method, and as shown in
FIGS. 6 and 7, the prosthesis 10 includes a plurality of
interconnected structural members 12 defining openings 14
therebetween and the beneficial agent 15 is dispensed only when the
dispensing element 150 and the structural members 12 within a
predetermined portion of the prosthesis 10 are aligned with each
other. Accordingly, in this preferred embodiment, dispensing
beneficial agent 15 ceases when the dispensing element 150 and the
structural members 12 of the prosthesis are not in alignment. To
this end, the method can include a detecting step to determine when
the dispensing element 150 is aligned with the structural members
12 of a prosthesis 10. The detecting step can be achieved by a
sensor 160 such as an optical detector, e.g., linear array detector
or infrared detector, ultrasound probe, temperature probe, camera,
capacitance meter, electrometer, hall-effect probe, and the like.
However, any sensor 160 known in the art for detection is within
the scope of the invention. Alternatively, a controller 170 may be
provided that is programmed with the structural member locations of
a predetermined portion of the prosthesis to be loaded with
beneficial agent. In this manner, the dispensing step is performed
by the dispensing element as operated by the programmed controller.
These aspects of the invention reduce or eliminate webbing and
bridging of beneficial agent across openings or gaps within the
structure of the prosthesis and minimizes waste. Furthermore, the
dispensing element 150 can be aligned such that the controlled
trajectory of each droplet is directed normal to the surface of the
prosthesis, or at an angle thereto. Similarly, the trajectory path
can be aligned to cross the central axis of the prosthesis, or be
aligned off-axis thereto.
[0067] According to another aspect of the invention, the method of
loading beneficial agent onto the prosthesis includes providing a
prosthesis including a tubular member having a central axis defined
along a length of the tubular member. This method further includes
dispensing beneficial agent from a dispensing element capable of
dispensing beneficial agent in discrete droplets and in a
controlled trajectory to a surface of the prosthesis, wherein the
controlled trajectory of beneficial agent is aligned so as not to
intersect the central axis of the tubular member.
[0068] For example, and for purpose of illustration and not
limitation, FIGS. 8a-8d depict various cross-sections of the
interventional device 10 of FIG. 6. In each cross-sectional view,
the trajectory path 152 of the discrete droplets 155 is aligned
"off-axis" so as not to pass through the central axis 11 of the
tubular member. Particularly, and as depicted in FIGS. 8a through
8d for purpose of illustration and not limitation, the trajectory
path 152 of the discrete droplets 155 is aligned tangentially
between an inner surface and an outer surface of the tubular wall
of the prosthesis 10. In this manner, likelihood of impact of a
discrete droplet 155 of beneficial agent 15 with a surface of the
prosthesis 11 is enhanced. If desired, however, alternative
off-axis trajectory path alignment can be used in accordance with
the invention.
[0069] With reference to FIGS. 8a-8d, the prosthesis provided by
the prosthesis providing step includes a tubular member having a
plurality of interconnected structural members 12 defining openings
14 therebetween, and further wherein the controlled trajectory 152
of each droplet is substantially tangential to a wall or surface of
the structural members 12 within the predetermined portion of the
prosthesis. In this regard, the controlled trajectory 152 of
beneficial agent 15 dispensed from the dispensing element 150 is
aligned such that it does not intersect the central axis of the
prosthesis. This process allows for greater coverage of the
structural elements, without requiring selective operation of the
dispensing element, if desired. That is, use of the "off-axis"
approach allows for enhanced loading of beneficial agent on the
prosthesis without selective or with only limited control of the
dispensing element if desired. In a preferred embodiment, however,
the dispensing element is at least controlled to terminate
dispensing when the trajectory path is not aligned with the solid
profile of the predetermined area to be loaded, e.g. axially beyond
either end 13 of the prosthesis 10, shown in FIG. 6. In particular,
the dispensing element is turned "on" only when the trajectory path
of beneficial agent will intersect the solid area swept out by 360
degrees rotation of the prosthesis. The dispensing element is
turned off when the trajectory path of beneficial agent would not
intersect or will miss the solid area and volume swept out by 360
degrees rotation of the prosthesis.
[0070] Alternatively, and in accordance with a preferred embodiment
of the invention, the "off-axis" method is performed using the
raster technique previously described. That is, with the trajectory
path 152 aligned off-axis from the central axis of the prosthesis
10, such as shown in FIGS. 8a-8d, discrete droplets can be
selectively dispensed from the dispensing element 150 only when
aligned with a structural member 12 of the prosthesis 10. In this
embodiment, the relative motion of the dispensing element 150 and
the prosthesis 10 define a dispensing path which includes a
sequential series of linear parallel passes that traverse back and
forth along one axis of the prosthesis. The relative motion
alternates between forward and backward, right to left, left to
right, or upward and downward, depending on the frame of reference.
A traversal or pass is completed when the relative motion changes
direction. That is, relative motion continues past the prosthesis
and then decelerates, stops, reversed direction and accelerates to
a constant velocity. After each pass, the position of the
dispensing element 150 is changed or incremented such that
additional drops of beneficial agent do not impact the same
location as the previously dispensed droplets during the subsequent
pass. Any degree of overlap may be permitted to achieve a desired
areal density of beneficial agent.
[0071] Alternatively, the relative motion of the dispensing element
and the prosthesis define a dispensing path which includes a single
continuous helix that wraps around the prosthesis and along its
length. The relative motion consists of continuously rotating, for
example, the prosthesis and then incrementally advancing the
dispensing element 150 axially along the prosthesis. Both axial and
radial motion preferably begin before the item is aligned with the
dispensing element to receive droplets of beneficial agent, so as
to enable acceleration of both axes to a constant velocity, and
continues beyond the prosthesis where both movements may
decelerate, and stop. After each rotation, the position of the
dispensing element or prosthesis relative to the dispensing element
is moved or incremented axially such that additional droplets
preferably do not impact in the same location. However, any degree
of overlap may be permitted to achieve a desired areal density of
beneficial agent.
[0072] The linear velocity during dispensing of droplets of
beneficial agent can be constant or can be varied in a controlled
way. Further, the preferable position of the droplet trajectory is
such that the droplets interact with the structural surfaces of the
prosthesis at or near the tangent to its curved solid surface.
[0073] In a preferred embodiment the dispensing path 154 includes a
series of parallel passes along a surface of the prosthesis. For
example and not limitation, the prosthesis provided can have a
tubular body prior to its deployment in a lumen, and each parallel
pass of the dispensing path 154 is parallel to the longitudinal
axis 11 of the prosthesis 10 as shown in FIG. 6a. After each pass,
the position of the dispensing element 150 or prosthesis 10 is
changed or incremented so that the discrete droplets 155 of
beneficial agent 15 are dispensed onto a surface of the prosthesis
10 that has not already been loaded. Alternatively, and as
previously noted, the parallel passes can define a helical pattern
around the longitudinal axis of the stent, wherein each pass is a
complete turn of the helical pattern. For purposes of illustration
and not limitation, the relative motion of the dispensing element
and the prosthesis can include continuously rotating the prosthesis
and incrementally advancing the dispensing element axially along
the length of the prosthesis. Preferably, after each rotation of
the prosthesis, the position of the dispensing element is
incrementally changed axially such that additional droplets of
beneficial agent that are dispensed from the dispensing element
load a surface of the prosthesis not already loaded by a prior
pass. In an alternative aspect of the invention, the prosthesis can
have a planar body prior loading, such that no rotation of the
planar member is required for loading of beneficial agent thereon.
The step of dispensing the beneficial agent onto the prosthesis
along the dispensing path can be repeated to provide multiple
passes along a predetermined portion of the prosthesis.
[0074] As noted above, the beneficial agent is selectively
dispensed from the dispensing element along the dispensing path in
a raster format. In this manner, the raster format can be achieved
by turning the dispensing element on and off at predetermined
intervals in response to a detector. Alternatively, the beneficial
agent can be selectively dispensed in a raster format by
programming a controller device that communicates with the
dispensing element to dispense the beneficial agent according to
the programmed data. A variety of fluid dispensers are available
and suitable for providing discrete droplets along a controlled
trajectory. For example, a suitable drop-on-demand jetting system
can be used, as shown in FIGS. 9 and 11, wherein discrete droplets
are selectively dispensed from a jetting head. In this manner, the
jet stream of discrete droplets can be turned on and off on demand,
and the flow rate of discrete droplets can be increased or
decreased as desired. Alternatively, if a charge-and-deflect device
is used, then a continuous stream of droplets will be generated,
and selected droplets will be deflected as is known in the art,
such as shown in FIG. 7, as described further below.
[0075] In an embodiment of the invention the prosthesis is a stent,
and as mentioned above, the fluid-dispenser is a fluid-jetting
device. In accordance with the preferred embodiment, a driver 120
continually advances the stent longitudinally along its axis at a
constant rate, to define a series of generally parallel passes 154
along the longitudinal axis 11 of the stent 10. The stent is the
incrementally rotated about its axis at the end of each pass. The
stent is rotated at about 1 degree to about 20 degrees about its
longitudinal axis, increments, and preferably is rotated at about 5
degree increments.
[0076] The fluid-jetting head is turned on to provide droplets of
beneficial agent whenever a stent strut or structural member is
detected immediately in front of the jetting head, or based on a
predetermined programmed pattern that corresponds to the stent
design, as mentioned above. By further providing controlled flow
rate dispensed from the jetting head, the beneficial agent can be
provided in a rastered format to confer the stent with a known
quantity of beneficial agent. If desired, the known quantity of
beneficial agent is dispensed to provide a uniform local areal
density based on changes in surface area. As used herein "local
areal density" refers to the amount of beneficial agent per unit
surface area of the stent or prosthesis.
[0077] For example and not limitation, a unit length of two
different struts having different strut widths could each be loaded
with an equal amount of beneficial agent by adjusting flow rate
accordingly. Contrastly, the flow rate of the jetting head can be
controlled along the progression of the stent to provide a first
portion 10b of the prosthesis 10 with a greater local areal density
and a second portion 10a of the prosthesis with a lower local areal
density, such as shown in FIG. 1. Similarly, the rate of relative
movement between the jetting head and the prosthesis can be varied
to control local areal density accordingly.
[0078] As noted above, the dispensing path 154 is defined by the
relative movement between the dispensing element and the
prosthesis. The relative movement between the dispensing element
and the prosthesis may be performed at a substantially constant
velocity, or alternatively at a varied velocity to alter local
areal density of beneficial agent, or intermittently. For an
example of varied velocity, and with reference to the embodiment of
FIG. 1a for purpose of illustration and not limitation, the linear
travel speed of the prosthesis under the fluid dispenser is
performed 50% faster during loading of beneficial agent on the
proximal and distal portions 10a and 10c of the prosthesis body to
decrease local areal density accordingly. Alternatively, the linear
travel speed of the prosthesis under the fluid dispenser may be 50%
slower during loading of beneficial agent on the mid region of the
prosthesis body to increase local areal density thereat.
[0079] Alternatively, rather than using a raster format, a vector
technique can be used wherein a first portion of the stent strut at
one end of the stent is positioned in front of the jetting head and
the jetting head is turned on. The jetting head is then left on to
dispense droplets of beneficial agent at a constant predetermined
frequency to provide a predetermined dispensing rate of agent. The
two-axis control system, described further below, is directed to
continuously move the stent, coordinating both axes simultaneously
so that the predetermined shape of the stent struts are advanced in
front of the jetting head. This movement continuously places the
beneficial agent on the struts of the first portion until the
desired surface of the stent has been positioned to receive
beneficial agent over the known surface area, and a predetermined
quantity of beneficial agent has been dispensed. The beneficial
agent is provided on the stent struts and the jetting head thereby
does not disperse beneficial agent in areas wherein metal has been
removed from the stent. This process may be repeated for subsequent
portions of the interventional device, such that known quantities
of beneficial agent are provided over each corresponding portion of
the interventional device. As with the raster format, flow rate or
rate of relative movement can be controlled to adjust local areal
density of beneficial agent as desired.
[0080] In yet another embodiment, the two-axis positioning system
is coupled to a charge-and-deflect jetting head. A
charge-and-deflect jetting head is capable of producing a rastered
pattern of droplets over a predetermined width of the stent. That
is, it is also in accordance with the invention to apply a surface
charge to selected droplets of beneficial agent dispensed from the
dispensing element. Preferably, if a positive surface charge is
applied to the beneficial agent, an antioxidant can be included in
the beneficial agent. In this manner, the antioxidant can help to
prevent the oxidation of a beneficial agent that might otherwise
oxidize when positively charged. Additionally, or alternatively,
other known techniques can be used to prevent or inhibit oxidation
of beneficial agent. The trajectory of charged droplets of
beneficial agent can be altered by a deflection field. For example,
an electrode 144 may be used to deflect the trajectory of
beneficial agent, which is charged by a charger 142, towards a
predetermined portion of the prosthesis as shown in FIG. 7. If
desired, a charge opposite that induced on the droplets of
beneficial agent can be applied to a predetermined portion of the
prosthesis to provide an electrostatic attraction between the
droplets of beneficial agent and the prosthesis for greater
accuracy and efficiency.
[0081] To effect predetermined loading of beneficial agent, or
coating thickness, several methods of controlling the two-axis
positioning system in coordination with control of the fluid
dispensing are possible so as to result in a precise deposition of
beneficial agent on the outer surface of the stent or prosthesis
10. First, the motor 122 that controls rotation of the prosthesis
about its longitudinal axis can be turned on to produce a constant
angular velocity. A second motor 124 is then controlled to advance
the prosthesis or stent in front of the dispensing element 150 at a
predetermined rate to generally describe a spiral or helix across
the longitudinal axis of the stent, where the pitch width, from
rotation to rotation, is the same as the raster width of the
dispensing element 150. When a charge-and-deflect dispensing
element is used, the surface of the prosthesis 10 or stent can be
exposed to the dispensing element 150 in a more rapid manner than
for the single drop wide raster pattern that is possible with the
drop-on-demand mode system. When the first stent strut is detected
to be present in front of the jet head 150, a bit-mapped pattern
that has been previously stored in memory 170 to describe the shape
of the struts is rastered out by providing appropriate charges on
selected droplets. Second, a linear array detector 160 with
resolution similar to the number of droplets in each raster line
can detect, by reflected or transmitted light, the presence of a
stent strut that is about to revolve in front of the jetted fluid
window. The data from this type of detector can then be transferred
to a shift register which produces the necessary raster data by
shifting the bit pattern out a bit at a time. With this method, no
predetermined bit-map is necessary, and any slight variations in
speed, edge detection or position may be automatically compensated.
This process may be repeated for subsequent portions of the
interventional device, such that known quantities of beneficial
agent are provided over each corresponding portion of the
interventional device.
[0082] Further in accordance with the invention, a system for
loading beneficial agent onto a prosthesis for delivery within a
lumen is provided. As shown in FIGS. 7 and 13, the system includes
a holder 110 for supporting a prosthesis and a fluid-dispenser
having a dispensing element 150 capable of dispensing beneficial
agent 15 in discrete droplets 155, each droplet having a controlled
trajectory.
[0083] The holder includes a mandrel or spindle 112 made of any
suitable material known in the art. Preferably, however, the
spindle 112 comprises a superelastic material, such as nitinol, or
any other material that has shape memory properties. Particularly,
manipulation of a stent holder made of stainless steel can result
in bending and deformation of the spindle. Such deformation causes
poor rotational accuracy and high run-out, e.g., 0.25-2.5 mm, from
one end of the spindle to the other end of the spindle. This can
cause a lower efficiency of loading beneficial agent onto a
prosthesis, and lower efficiency of droplet interaction with the
prosthesis because the position of the stent under the jetting head
varies as the run out varies. Superelastic materials generally have
properties that are able to absorb and recover from up to 8% strain
force. Thus, advantageously, nitinol provides a more resilient
spindle capable of undergoing repeated manual stent mounting
without the plastic deformation that occurs with a stainless steel
spindle design.
[0084] For purpose of illustration and not limitation, and as shown
in FIG. 13, a nitinol spindle 112 may be made using a centerless
grinding technique to obtain high concentric accuracy. Despite this
grinding process, the centerline of the small diameter part of the
spindle (e.g., 0.5 mm diameter) can vary a few degrees from the
centerline of the intermediate diameter section (e.g., 2 mm
diameter). This variance can be removed by heating the spindle near
the junction of the small and intermediate diameter section and
bending it to remove most of the residual run out. Upon cooling,
the spindle, shown in FIG. 13, assembly retains its new position.
The final run out on an exemplary spindle after using these
techniques was about 0.051 mm.
[0085] The system also includes a driver such as a driver assembly
120 to create relative movement between the holder 110 and the
dispensing element 150, and a controller 170 in communication with
the driver 120 to define a dispensing path of relative movement
between the dispensing element 150 and the holder 110. The
controller also communicates with the dispensing element 50 for
selectively dispensing beneficial agent in a selected format along
the dispensing path onto a selected portion of the prosthesis 10
supported by the holder 10. In one aspect of the invention the
holder 110 supporting the prosthesis 10 is moveable while the
dispensing element 150 remains stationary during dispensing of
beneficial agent 15. However, in another aspect of the invention
the holder 110 supporting the prosthesis 10 remains stationary
while the dispensing element 150 moves along the dispensing
path.
[0086] Alternatively, both the holder 110 and dispensing element
150 are moveable. In another aspect of the embodiment, as
previously described, the system includes a detector 160 to detect
when the dispensing element 150 is aligned with the predetermined
portion of the prosthesis 10. Various known components can be used
in combination for construction of the system of the present
invention. For example, jetLab System II from MicroFab Technologies
of Plano, Tex., as modified to include the desired features of the
invention can be used.
[0087] In yet another embodiment of the invention, a determination
of the quantity of beneficial agent dispensed over a given or known
surface area can be established. According to one aspect, a
predetermined ratio of an identifiable marker is added to the
beneficial agent and both the beneficial agent and the marker are
loaded onto the prosthesis. Subsequently, the amount of
identifiable marker loaded onto the prosthesis is detected to
determine the amount of corresponding beneficial agent loaded onto
the prosthesis. In one aspect of the invention, the identifiable
marker includes radiopaque material. After loading the radiopaque
material with the beneficial agent onto the prosthesis, the
prosthesis is imaged and an intensity value is measured to
determine the amount of beneficial agent loaded thereon and thus
local areal density. The identifiable marker in this aspect can
also include a fluorescent dye, e.g., coumarin dye. In another
aspect of the invention, the identifiable marker includes charged
particles, for example and not limitation, protons or electrons.
After loading the marker and beneficial agent onto the prosthesis
the detecting step includes measuring a charge build-up on or
current flow from the prosthesis resulting from the charged
particles. The charge build-up or current flow therefore generally
corresponds to the amount of beneficial agent loaded onto the
prosthesis. Alternatively, because the fluid jetting technology of
the present invention is inherently digital, the quantity of
beneficial agent dispensed can be determined by counting the
droplets that have been jetted or dispersed.
[0088] In yet another alternative, the amount of beneficial agent
loaded can be measured more generally by weighing the stent before
the jetting operation and then after the jetting operation. The
weight difference corresponds to the drug loaded with the
concentration being a function of the jet flow rate along the
length of the stent. Yet another method is to integrate the charge
build-up on the prosthesis when a charge-and-deflect system is
used. Since each droplet in a charge-and-deflect jetting system has
had a surface charge injected onto it to enable the droplet to be
deflected in an electrostatic field, either the loss of charge at
the charging electrode or the accumulation of charge on the
prosthesis can be integrated over time to determine the total
volume of fluid that has accumulated on the surface of the
device.
[0089] Also in accordance with the invention, an on-board
spectrometer may be utilized for monitoring the beneficial agent
concentration on the jetter reservoirs as a function of time. It is
desirable to load beneficial agent such as a drug at a constant
concentration. However, due to the evaporation of solvent during
the loading process, the concentration of drug will increase.
Advantageously, a spectrometer can be configured with a pump to add
solvent to the drug such that a constant absorbance on the
spectrometer is maintained. The constant absorbance level of the
spectrometer is pre-set to monitor an appropriate wavelength. The
maintenance of a constant absorbance reading on the spectrometer by
the addition of solvent translates to the maintenance of a pre-set
drug concentration.
[0090] For drop-on-demand jetting systems, this same drug
quantification concept can be utilized by adding a constant voltage
charging electrode adjacent to the nozzle of the dispenser so as to
add a polar charge to each droplet. The coating on the stent, if an
insulator, will act as a capacitor to the charge. This detection
technique will be able to detect charge build up if a small leakage
path is provided or if a second reference surface is provided
against which to compare charge build up. Other alternative
techniques can be used. For example, if a metal mandrel is present
inside the stent it may be used to monitor any lost droplet or
splash. The charge that directly transfers to this "electrode" will
create an opposite polarity current to the charge presented to the
insulated coated surface of the stent.
[0091] For each of these detection techniques described above, an
appropriate detector can be incorporated in the system of FIG. 7,
preferably in communication with controller 170.
[0092] In accordance with another aspect of the invention, a second
beneficial agent or multiple beneficial agents can be loaded onto
the prosthesis as described above. Therefore, further in accordance
with the invention, an interventional device comprising a
prosthesis loaded with a plurality of discrete droplets of a first
beneficial agent and a plurality of discrete droplets of a second
beneficial agent is provided, such as by using the system and
method shown in FIG. 9.
[0093] Particularly, the method described in detail above for one
beneficial agent can be modified to allow for loading multiple
beneficial agents onto a prosthesis, which might ordinarily lead to
undesirable results when using conventional loading techniques. For
example and not limitation, the first beneficial agent and the
second beneficial agent may have different physical and/or chemical
characteristics preventing the beneficial agents from being capable
of dissolving in the same solvent, or at the same pH or
temperature. In particular, the first beneficial agent can be
dissolved in a solvent that is immiscible with the solvent in which
the second beneficial agent is dissolved. Alternatively, the first
beneficial agent and the second beneficial agent may be
incompatible with each other. In particular, the first beneficial
agent and the second beneficial agent can be undesirably chemically
reactive or may have undesirably different release rates (or
contrarily, undesirably similar release rates). Additionally, the
first and second beneficial agents can simply be detrimental to
each other, e.g., one of the beneficial agents may degrade the
efficacy of the other beneficial agent. Thus, although loading the
particular multiple beneficial agents onto the same surface of a
prosthesis can be desired it often may be problematic due to some
incompatibility when using a conventional loading technique. In
accordance with the present invention, a method of loading such
beneficial agents and an interventional device for the delivery of
such beneficial agents is provided.
[0094] As noted above, the beneficial agents are loaded in a
plurality of discrete droplets on the surface of the prosthesis.
The discrete droplets of multiple beneficial agents are preferably
loaded onto the prosthesis as unmixed droplets to provide an
interspersed pattern or alternatively, the unmixed droplets of
beneficial agent can be loaded onto the prosthesis to provide an
overlapping pattern of the first beneficial agent and the second
beneficial agent. In this manner, the edges of the droplets overlap
or alternatively, a larger surface of the droplet overlaps other
droplets to provide a layering effect, as depicted in FIG. 10.
[0095] Multiple fluid-dispensers are in accordance with the
invention, wherein each beneficial agent to be loaded onto the
prosthesis is dispensed from a distinct dispensing device. For
purpose of illustration and not limitation as shown in FIG. 9, a
first dispenser 150 is provided with a first beneficial agent 15'
dissolved in a solvent that is compatible for that particular first
beneficial agent. Further, a second fluid-dispenser 150'' is
provided with a second beneficial agent 15'' that is different from
the first beneficial agent 15', and requiring a different solvent
for compatibility. For example, the first beneficial agent could be
a water-soluble agent, whereas the second beneficial agent could be
a water-insoluble agent, each requiring a different solvent.
Accordingly, both beneficial agents are loaded onto the same
surface of the prosthesis without problems arising from their
immiscibility.
[0096] Where two fluid-dispensers are used to load the multiple
beneficial agents onto the prosthesis, the trajectories of discrete
droplets corresponding to each of the first beneficial agent and
the second beneficial agent can be aligned such that the droplets
from each beneficial agent combine and mix prior to their being
loaded on the prosthesis. In this manner, the first and second
beneficial agent can form a third beneficial agent which is loaded
onto the prosthesis. For purpose of illustration and not
limitation, the first beneficial agent may be
bisphenol-A-diglycidyl ether and the second beneficial agent can be
triethylenetetramine. Upon combination of the first beneficial
agent and the second beneficial agent, a cross linked coating is
formed to provide a third beneficial agent. In yet another
illustrative example, the first beneficial agent can be
bisphenol-A-diglycidyl ether and paclitaxel and the second
beneficial agent can be triethylenetetramine. Upon the combination
of the two controlled trajectories of beneficial agents, a third
beneficial agent is formed, a cross-linked coating entrapping
paclitaxel, which is loaded on the prosthesis. Alternatively, the
discrete droplets of the first and second beneficial agent can be
aligned along trajectories to mix on the surface of the
prosthesis.
[0097] As noted above, the beneficial agent can include a drug and
polymer mixture. In accordance with the method of the invention,
the first and second beneficial agents can correspond to
drug-polymer mixtures having different concentrations of polymer to
effect different release rates of the particular drug in each
beneficial agent. For example, the drug-polymer mixture having a
higher concentration of polymer would have a slower release of the
drug within the lumen than a drug-polymer mixture having a lower
concentration. Alternatively, rather than providing drug-polymer
mixtures having different polymer concentrations to provide
different release rates, it is also possible to dispense beneficial
agents using different polymers or other binders, wherein the
specific polymer or binder has different diffusivity or affinity to
assure delivery of the beneficial agents at different rates. Thus,
in accordance with the invention, multiple beneficial agents can be
released at rates appropriate for their activities, such that the
prosthesis of the invention has multiple beneficial agents which
elute off the prosthesis at desired rates.
[0098] For example, a cationic phosphorylcholine-linked polymer
which has a higher affinity for anionic therapeutic agents can be
blended and dispersed as a first beneficial agent and lipophilic
phosphorylcholine-linked polymer can be blended with lipophilic
drugs as the second beneficial agent to effect different release
rates respectively.
[0099] In yet another embodiment of the invention, one of the first
and second beneficial agents loaded onto the prosthesis can be more
hydrophobic or less water-soluble than the other. Thus, in
accordance with the invention is provided a prosthesis including
first and second beneficial agents wherein one of the beneficial
agents is more hydrophobic or less water soluble than the other. In
this manner, the more hydrophobic beneficial agent acts as a water
barrier or hydration inhibitor for the less hydrophobic beneficial
agent, thereby reducing the release rate of the less hydrophobic
beneficial agent as disclosed in U.S. Provisional Patent
Application 60/453,555 and PCT/US03/07383, each of which was filed
on Mar. 10, 2003, and each of which is incorporated herein by
reference thereto.
[0100] In addition to providing a prosthesis having multiple
beneficial agents which are delivered at unique or desired rates,
according to another aspect of the invention, the first beneficial
agent can be dissolved in solvent wherein the second beneficial
agent causes the first beneficial agent to precipitate out of the
solvent. For example and not limitation, the first beneficial agent
may be rapamycin dissolved in ethanol, and the second beneficial
agent may be water. Upon droplet combination using the method and
system of the invention, the rapamycin will precipitate within the
droplet and be deposited on the prosthesis as a
microprecipitate.
[0101] In yet another aspect of the invention, at least one of the
first and second beneficial agents can be mixed with a binder prior
to being loaded onto the prosthesis. Further in accordance with
this aspect one of the beneficial agents can be a curative agent
for curing the binder on the prosthesis with the beneficial agent
mixed therein. For example, see Example 4 below.
[0102] As noted above, one of the beneficial agents can be a
solvent for the other beneficial agent. Thus, in accordance with
the invention, the first beneficial agent, e.g., a drug, polymer,
or a combination thereof, can be loaded onto the prosthesis, and
subsequently the second beneficial agent, i.e., a solvent, can be
loaded onto the prosthesis so as to redistribute the first
beneficial agent more uniformly along the prosthesis.
[0103] As also noted above, the prosthesis can include at least one
reservoir or cavity or trough therein. For purpose of illustration
and not limitation, computer controlled profiles of a laser cut
stent can be utilized to precisely deposit beneficial agent into
the laser cuts on the stent struts. For example, a longitudinal
trough can be laser cut, etched, or otherwise formed into the
strut, such as in the curve or bend of the strut for instance. In
accordance with a preferred aspect of the invention, the cavity or
trough is provided with a contoured cross-sectional profile for
retention and elution of beneficial agent therein. Particularly,
and as depicted schematically in FIG. 12, the cross-sectional
profile of the cavity or trough 16 includes a smaller dimension at
the interface with the strut surface, so as to define a mouth 17 of
the trough 16, and a larger internal cross-dimension of the trough
to define a reservoir 18. FIG. 12 shows one such embodiment,
wherein mouth 17 is defined for reservoir 18 of trough 16. Use of
the fluid jet system and method of the present invention thus
allows for beneficial agent to be loaded into the mouth 17 of
trough 16, without the entrapment of air within the reservoir 18.
An appropriate volume of beneficial agent is deposited in the laser
cut profile to at least partially fill the reservoir 18. In this
respect, beneficial agent that is deposited in the longitudinal
trough can include a combination of drugs or a combination of
polymers or a combination of drugs and polymers in different
layers. Furthermore, different layers of polymer and/or drug having
different concentrations, or different drug elution rates can be
loaded therein. Additionally, an interim polymer and/or final
polymer overcoat can be applied over the beneficial agent. Such a
deposition configuration in combination with cavities is
particularly beneficial for minimizing delamination of the
polymer-drug layers, and also provides versatility in controlling
drug elution and the generation of various combinations of drug
release patterns. A computer profiling approach is also useful to
coat drug and polymer layers on the distal and proximal edges of
the stent.
[0104] In accordance with another aspect of the invention, one or
more of the reservoirs or cavities or troughs is loaded with a more
hydrophilic first beneficial agent and then a second more
hydrophobic beneficial agent is loaded onto the first beneficial
agent within the cavity or reservoir in a manner as described
above.
[0105] Further in accordance with the invention, using the method
and systems described above, a first beneficial agent loaded onto
the prosthesis can have a first local areal density and a second
beneficial agent loaded onto the prosthesis can have a second local
areal density. As used herein, "areal density" refers to the amount
of beneficial agent per unit surface area of a selected portion of
the prosthesis. "Local areal density" refers to the dosage of
beneficial agent per local surface area of the prosthesis The local
areal density of the first beneficial agent and the local areal
density of the second beneficial agent can be uniform across each
respective portion to define stepped changes in local area density
as depicted in FIG. 1b or can be varied across a selected portion
of the prosthesis to define gradients of local area density, as
depicted in FIG. 1c. Accordingly, an interventional device is
provided having a prosthesis that is at least partially loaded with
beneficial agent having a local areal density that is varied along
a selected portion of the body of the prosthesis.
[0106] In accordance with a preferred embodiment, the prosthesis
has a tubular body when deployed in a lumen. Preferably, the
tubular body includes a first and second portion at least partially
loaded with beneficial agent such that the first portion has a
first local areal density and the second portion has a second local
areal density. Each portion may be defined as a preselected length
of the prosthesis. Alternatively, as shown in FIG. 1b, the first
portion can be defined by a selected set of interconnected
structural members and the second portion can be defined as a
second set of interconnected members e.g., connectors elements or
ring-elements. For example and not limitation, at least one of the
first and second set of selected interconnected elements can define
at least one ring-shaped element extending around the circumference
of the prosthesis.
[0107] In another embodiment of the invention, the local areal
density is varied as a continuous gradient along a selected portion
of the prosthesis as shown in FIG. 1c. Accordingly, in one aspect
of the invention the local areal density of beneficial agent is
varied such as to provide a prosthesis having a local areal density
of beneficial agent at the ends of the prosthesis that is different
than the local areal density of beneficial agent at an intermediate
section of the prosthesis. For purpose of illustration and not
limitation, the local areal density of beneficial agent at the
intermediate section of the prosthesis can be greater than that at
the proximal and distal ends of the prosthesis as shown in FIG. 1c.
Alternatively, the proximal and distal ends of the prosthesis can
have a greater local areal density of beneficial agent than that on
the intermediate section of the prosthesis. In a preferred
embodiment of the invention, the varied local areal density of
beneficial agent corresponds to the location of a lesion when the
prosthesis is deployed within a lumen. For example, the prosthesis
can be loaded to have a greater local areal density of beneficial
agent along a preselected portion of the prosthesis that
corresponds to the location of the lesion when the prosthesis is
deployed in a lumen. Thus, targeted therapy may be achieved with
the interventional device of the present invention.
[0108] In accordance with the invention, the local areal density
can be varied by varying the relative rate in which beneficial
agent is loaded to a selected location along the prosthesis. To
this end, the frequency in which the droplets of beneficial agent
are applied along a unit length of the dispensing path to the
prosthesis is varied. Alternatively, the relative rate of loading
beneficial agent can be varied by varying the relative movement
between the dispensing element and the prosthesis. Another
alternative for varying the relative rate of loading beneficial
agent is to vary the amount of beneficial agent per droplet
dispensed from the dispensing element. Other alternatives for
varying the local areal density of beneficial agent loaded onto the
prosthesis include mixing the beneficial agent with a binder and
varying the ratio of beneficial agent to binder. Alternatively, the
amount of the mixture of beneficial agent and binder that is
applied to the prosthesis can be varied to achieve a varied local
areal density of beneficial agent. Other methods of varying the
local areal density of beneficial agent known in the art may be
used.
[0109] As noted above, the beneficial agent is at least partially
loaded onto a surface of the prosthesis. Further in accordance with
the invention the prosthesis includes a first surface and a second
surface that are at least partially loaded with beneficial agent.
In one embodiment of the invention, the first surface and the
second surface each correspond to one of the inner surface and the
outer surface of the prosthesis. Thus, according to this particular
embodiment, beneficial agent, as defined above, is loaded onto the
inner or luminal surface of a prosthesis as well as the outer
surface of the prosthesis. The method described above can be used
for this aspect of the invention, wherein the beneficial agent is
loaded on the inner surface of the prosthesis by inserting a fluid
dispensing element within the inner diameter of the prosthesis, or
by dispensing beneficial agent 15 diametrically across the
prosthesis 10 between structural members 12 to impact the inner
surface on the opposite side of the prosthesis 10 as shown in FIG.
11. In this regard, the dispensing element 150'' is aligned so that
the controlled trajectory 152'' of discrete droplets 155'' of
beneficial agent optimally intersect with the inner surfaces of the
structural features of the prosthesis 10 and not intersect with the
structural features of the outer surface of the prosthesis. For
purposes of illustration and not limitation, for a prosthesis
comprising an odd number of radial repeats in the pattern of
structural features, the preferred alignment of the dispensing
element is orthogonal to the central axis of the prosthesis and in
a plane that intersects the central axis of the prosthesis.
However, for a prosthesis comprising an even number of radial
repeats in the pattern of structural features, the preferred
alignment of the dispensing element to the prosthesis is orthogonal
to the central axis of the prosthesis, but in a plane that does not
intersect the central axis of the prosthesis. As another example,
for a prosthesis including a tubular member comprising multiple
radially and axially repeating structural elements, the preferred
alignment of the dispensing element can be determined by assessing
the shadow cast by the foreground or outer structural elements on
the background or inner structural elements. The preferred plane to
align the dispensing element can be determined by assessing the
plane in which the maximum amount of unobstructed inner surface is
presented upon rotation of the tubular member.
[0110] In accordance with this aspect of the invention, the
relative motion of the dispensing element and the prosthesis can be
coordinated to enable a preprogrammed "raster" image of the
position or locations of the structural elements of the inner
surface. Alternatively, the vector pattern of the structural
elements may be preprogrammed, as previously described. Also, in
accordance with the invention, the beneficial agent is dispensed
from the dispensing element along a controlled trajectory that is
substantially tangential to or near the outer surface of the
prosthesis and is loaded on the inner surface of the structural
elements of the prosthesis.
[0111] In this aspect of the invention, the interventional device
can be designed to provide combination therapy of beneficial agents
to targeted locations. For example and not limitation, the
particular beneficial agent loaded to the luminal or inner surface
of the prosthesis can be intended for systemic release, whereas the
particular beneficial agent loaded onto the outer surface of the
prosthesis is intended for release into the wall of the lumen. In
accordance with one aspect of the invention, the beneficial agents
loaded onto the luminal side or inner surface of the prosthesis
include, without limitation, antiplatelet agents, aspirin, cell
adhesion promoters, agents that promote endothelial recovery,
agents that promote migration, and estradiol. The beneficial agents
loaded onto the outer surface of the prosthesis include without
limitation, anti-inflammatories, anti-proliferatives, smooth muscle
inhibitors, cell adhesion promoters, and the rapamycin analog
ABT-578, i.e.,
3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,1-
3,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R-
)-2-[(1S,3R,4R)-3-methoxy-4-tetrazol-1-yl)cyclohexyl]-1-methylethyl]-10,21-
-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxa-
azacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone;
23,27-Epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4-
H,6H,3H)-pentone
[0112] In accordance with another embodiment of the invention, the
first surface of the prosthesis is defined by a plurality of
interconnecting structural members. Accordingly, the first surface
can include a first selected set of structural members, e.g., a
connector member, and the second surface can include a second
selected set of the structural members, e.g., a ring-shaped element
extending around the circumference of the prosthesis.
[0113] As noted above, the beneficial agent is loaded onto the
prosthesis to provide a controlled local areal density across a
length of the interventional device. That is, it may be desirable
to provide a greater concentration of beneficial agent at one
portion of a prosthesis and a lower concentration, or perhaps no
beneficial agent, at another portion of the prosthesis. For
example, in one embodiment, a greater local areal density can be
provided at a first portion, e.g., intermediate portion 10b, of a
stent 10, as shown in FIG. 1a, while providing a lower local areal
density of beneficial agent to a second portion, e.g., one or both
end portions (10a, 10c), of the stent 10. In accordance with the
present invention, each of the first and second portions of the
prosthesis may be defined by any of a variety of patterns or
selected portions of the prosthesis. For example, the first portion
of the prosthesis can be defined by longitudinal connectors whereas
the second portion of the stent is defined by annular rings, or
vice versa, as illustrated in FIG. 6.
[0114] In accordance with another aspect of the present invention,
the interventional device includes a first prosthesis and a second
prosthesis in combination to define an overlapping portion and at
least one non-overlapping portion. For example, and as embodied
herein, FIG. 2 or 3 present a schematic representation of a nested
interventional device including a first prosthesis 20 and a second
prosthesis 30 configured to be deployed in an overlapping
relationship. The interventional device, however, can optionally
include more than two prostheses in combination, if desired. Such
interventional devices 50 include but are not limited to nested
stents and modular bifurcated stents. For purpose of illustration
and not limitation, FIG. 2 shows a first prosthesis 20 having a
first portion 20a and a second portion 20b and a second prosthesis
30 having a first portion 30a and a second portion 30b. As shown
schematically, the beneficial agent distribution profile includes a
first local areal density of beneficial agent on one of the first
and second portions of one or both of the first prosthesis and the
second prosthesis. For example and not by limitation, the first
portion 20a of the first prosthesis 20 has half the local areal
density of beneficial agent as compared to the second portion 20b
of the first prosthesis 20. The first portion 30a of the second
prosthesis 30, likewise, has half the local areal density of
beneficial agent compared to the second portion 30b of the second
prosthesis 30. In this manner, when the ends of two stents are
superimposed or deployed in an overlapping relationship 25 during a
procedure, the local areal density of beneficial agent along the
interventional device 50 is controlled so as to be uniform. If
desired, alternative concentrations can be provided on each portion
so as to provide the desired effect in combination.
[0115] In accordance with the invention, as shown in FIG. 3, a
controlled local areal density of beneficial agent is thus provided
across a length of the interventional device 50 upon combination of
the first prosthesis having first portion 20a and second portion
20b with the second prosthesis having first portion 30a and second
portion 30b, as shown in FIG. 2. In particular, as shown in FIG. 3,
the overlapping segment 25 of first prosthesis 20 and the second
prosthesis 30 has an equal local areal density of beneficial agent
as compared to non-overlapping segments 20b and 30b.
[0116] Alternatively, the beneficial agent distribution profile for
the interventional device may be controlled to include any of a
variety of desired patterns. For example, the interventional device
can have a decreased local areal density of beneficial agent on the
distal and proximal ends of each prosthesis body, as noted above.
This profile is highly desirable in preventing adverse dosing of
beneficial agent if multiple prostheses are placed in combination
with each other but still provides for decreased dosage of the
extreme ends of the interventional device as a whole.
Alternatively, as embodied herein, the beneficial agent
distribution profile can provide a controlled local areal density
that is uniform along the length of first prosthesis and second
prosthesis in combination, or multiple prostheses in combination.
Alternatively, in accordance with the invention, the beneficial
agent distribution profile provides a controlled local areal
density that is varied along the length of the first prosthesis and
the second prosthesis in combination, or multiple prostheses in
combination.
[0117] For illustration purposes, overlapping or nested prostheses,
as shown in FIG. 3, can have beneficial agent distribution profiles
such that the controlled local areal density of beneficial agent of
a non-overlapping segment is in fact greater than the controlled
local areal density of beneficial agent of a overlapping segment.
Similarly, the alternative can also be true; that a overlapping
segment is controlled to have a greater or different local areal
density of beneficial agent than a non-overlapping segment.
Advantageously, this feature also enables selective dosing of
beneficial agent to a targeted area when using multiple prostheses
in combination, as well as a single prosthesis alone, Selective
dosing of beneficial agent to a targeted area means that the
beneficial agent can be applied to the prosthesis or prostheses in
combination such that the desired beneficial agent is loaded onto
the prosthesis in a selective pattern so that the beneficial agent
or beneficial agents are released from the prosthesis in close
proximity to a targeted location, Fluid jetting as previously
described is particularly preferred for selective dosing.
[0118] In accordance with the present invention, and as embodied
schematically in FIG. 5, a bifurcated interventional device also
can be provided, which includes a first prosthesis 20' and a second
prosthesis 30' in combination to define an overlapping portion 50'
and non overlapping portions 20b', 30b'. For purposes of
illustration and not limitation, FIG. 4 shows a first prosthesis
20' having a first portion 20a' and a second portion 20b', and a
second prosthesis 30' having a first portion 30a' and a second
portion 30b'. As shown for purpose of illustration and not
limitation, the beneficial agent distribution profile includes a
first local areal density of beneficial agent on one of the first
and second portions of one or both of the first prosthesis 20' and
the second prosthesis 30'. For example, and not by limitation, the
first portion 20a' of the first prosthesis 20' has half the local
areal density of beneficial agent as compared to the second portion
20b' of the first prosthesis. The first portion 30a' of the second
prosthesis 30' has half the local areal density of the second
portion 30b' of the second prosthesis 30'. In accordance with the
present invention, as shown in FIG. 5, a controlled local areal
density of beneficial agent is thus provided across a length of the
bifurcated interventional device 50 upon combination of the first
prosthesis having first portion 20a' and second portion 20b' with
the second prosthesis having first portion 30a' and second portion
30b', as shown in FIG. 4.
[0119] Another feature of the present invention includes applying a
layer of base material on a selected portion of the prosthesis
described above. The beneficial agent is loaded onto the base
material layer according to the methods described above. The base
material layer preferably defines a pattern for loading the
beneficial agent onto the prosthesis.
[0120] The present invention also encompasses, for any of the
embodiments disclosed, the application of a rate-controlling
topcoat over the beneficial agent loaded prosthesis for further
controlling or sustaining the release of beneficial agent. The
rate-controlling topcoat may be added by applying a coating layer
posited over the beneficial agent loaded prosthesis. The thickness
of the layer is selected to provide such control. Preferably, the
overcoat is applied by fluid-jet technology. Advantageously, fluid
jetting an overcoat such as a polymer overcoat allows a thinner and
more uniform layers. However other conventional methods can be used
such as other fluid-dispensers, vapor deposition, plasma
deposition, spraying, or dipping, or any other coating technique
known in the art.
[0121] The present invention also provides a method for
manufacturing an interventional device for delivery of beneficial
agent. This method comprises the steps of providing a first
prosthesis to be deployed within a lumen; providing a second
prosthesis configured to be deployed in an overlapping relationship
with the first prosthesis, the first prosthesis and the second
prosthesis in combination defining at least one non-overlapping
segment and an overlapping segment; and loading the first
prosthesis and the second prosthesis with beneficial agent to
provide a controlled local areal density along a length of the
first prosthesis and the second prosthesis in combination. The
method described in detail above is preferred for such loading
step.
[0122] The present invention also provides a method of delivering
beneficial agent. In accordance with this method, as described in
detail in conjunction with the description of the interventional
device of the present invention above, the method comprising the
steps of providing a first prosthesis having a tubular body when
deployed in a lumen; providing a second prosthesis having a tubular
body when deployed in a lumen; loading at least one of the first
prosthesis and the second prosthesis with beneficial agent;
deploying the first prosthesis into a lumen; deploying the second
prosthesis into the lumen to define in combination with the first
prosthesis at least one non-overlapping segment and an overlapping
segment; wherein the beneficial agent is loaded onto at least one
of the first prosthesis and the second prosthesis to provide a
controlled local areal density of beneficial agent across a length
of the first prosthesis and the second prosthesis when deployed.
The method described in detail above is preferred for such loading
step.
[0123] The present invention will be further understood by the
examples set forth below, which are provided for purpose of
illustration and not limitation.
EXAMPLES
Example 1
Jetting of Reactive Substances
[0124] The components of a commercial two-part epoxy formulation
are mixed by the jetting process and applied to a surface to form a
coating. In a formulation manufactured by Buehler, Lake Bluff Ill.,
one part is a liquid "epoxide resin" that contains 4,4'
isopropylidenediphenol epichlorohydrin resin and butyl glycidyl
ether. The second part is a liquid "hardener" that contains
diethylene triamine, triethylene tetramine, and
polyoxypropylenediamine. In the jetting process, one reagent jet
system (A) is loaded with epoxide resin and a second jetting system
(B) is loaded with hardener. The jets are aligned such that the
droplets emanating from each jet combine in midair and travel to
the target device to form a crosslinked coating, after a curing
time of 2-8 hours. The volume of a droplet emanating from jet A is
5 times larger than the volume of a droplet emanating from Jet B
and the total number of droplets dispensed from each jet are
approximately equal.
Example 2
Jetting of Reactive Substances
[0125] The components of a commercial two-part epoxy formulation
are mixed by the jetting process and applied to a surface to form a
coating. In a two part commercial formulation manufactured by
Buehler, Lake Bluff Ill., one part is a liquid "epoxide resin"
which contains 4,4' isopropylidenediphenol epichlorohydrin resin
and butyl glycidyl ether. The second part is a liquid "hardener"
that contains diethylene triamine, triethylene tetramine, and
polyoxypropylenediamine. In the jetting process, one reagent jet
system (A) is loaded with epoxide resin and a second jetting system
(B) is loaded with hardener. The jets are aligned such that the
droplets emanating from each jet combine in midair and travel to
the target device to form a crosslinked coating, after a curing
time of 2-8 hours. The volume of a droplet emanating from jet A is
4 times larger than the volume of a droplet emanating from Jet B
and the total number of droplets dispensed from each jet are
approximately equal. This coating cures at a faster rate than the
coating described in example 1.
Example 3
Jetting of Reactive Substances
[0126] The components of a commercial two-part epoxy formulation
are mixed by the jetting process and applied to a surface to form a
coating. In a two part commercial formulation manufactured by
Buehler, Lake Bluff Ill., one part is a liquid "epoxide resin"
which contains 4,4' isopropylidenediphenol epichlorohydrin resin
and butyl glycidyl ether. The second part is a liquid "hardener"
that contains diethylene triamine, triethylene tetramine, and
polyoxypropylenediamine. In the jetting process, one reagent jet
system (A) is loaded with epoxide resin and a second jetting system
(B) is loaded with hardener. The jets are aligned such that the
droplets emanating from each jet combine in midair and travel to
the target device to form a crosslinked coating, after a curing
time of 2-8 hours. The volume of a droplet emanating from jet A is
approximately equal to the volume of a droplet emanating from Jet
B, but the total number of droplets dispensed from jet A is 4 times
more than from jet B.
Example 4
Formation of a Crosslinked Network Containing Biologically Active
Agents
[0127] One reagent jet system (A) is loaded with a liquid epoxide
resin and a solubilized formulation of the drug, paclitaxel, 20% by
weight with respect to the epoxide resin. A second jetting system
(B) is loaded with hardener similar to that described in example 1
combined with an equal weight or less of a biocompatible polymer.
One example of such a species is a phosphorylcholine linked polymer
of the general formula
poly(MPC.sub.w:LMA.sub.x:HPMA.sub.y:TSMA.sub.z), where MPC is
2-methacryoyloxyethylphosphorylcholine, LMA is lauryl methacrylate,
HPMA is hydroxypropyl methacrylate and TSMA is
trimethoxysilylpropyl methacrylate. This polymer is dissolved in a
solvent such as chloroform. The jets are aligned such that the
droplets from each jet combine in midair and travel to the target
device to form a crosslinked coating entrapping the drug and
polymer. The volume of a droplet emanating from jet A is 5 times
larger than the volume of a droplet emanating from jet B and the
total number of droplets dispensed from each jet are approximately
equal. The coating is heated for 4 hours at 70 degrees C. to cause
crosslinking of the phosphorylcholine-linked polymer predominantly
with itself by means of the trimethoxysilane groups, and
simultaneously accelerating the curing of the epoxide resin with
the hardener.
Example 5
Formation of a Drug Microprecipate
[0128] One reagent jet system (A) is loaded with rapamycin
dissolved in ethanol. A second jetting system is loaded with water.
The droplet volume of one drop emanating from jet A is 50
picoliters and the droplet volume of one drop emanating from Jet B
is 150 picoliters. The jets are aligned such that the droplets from
each jet combine in midair and travel to the target device. During
the droplet combination the rapamycin will precipitate within the
droplet and be deposited on the target surface as a
microprecipitate.
Example 6
Loading of Drug onto a Polymer Base-Coated Coronary Stent
[0129] In a demonstration of feasibility, a stock jetting solution
of 20 mg/ml ABT-578+4 mg/ml phosphorylcholine-linked methacrylate
polymer (PC) in isobutanol was prepared. A fluid jetting system
manufactured by MicroFab Technologies of Plano, Tex. was programmed
to jet 75 micrograms of drug evenly over a 1.4.times.11 mm OC
BiodivYsio stent to obtain an areal density of 5 micrograms per
linear mm. Jetting of 21,888 drops into a vial containing 10 ml of
isobutanol gave 77 micrograms of ABT-578 as determined
spectrophotometrically at 278 nm. Under these conditions, 1 drop
was 170-180 picoliters and had a diameter between 67 and 70
microns. The stent contained a base coating of
phosphorylcholine-linked methacrylate polymer (PC). It was mounted
on a fixture that included a mandrel that provided for controlled
rotation (.theta.) about a central axis coaxial with the stent and
a stage that provided for lateral movement (X) along the axis of
the stent. The motion control was set up to rotate the stent a
total of 720 degrees. A view orthogonal to the axis of the rotating
stent showed two possible tangential off-axis positions,
approximately 50 microns inside a point tangent to the outer
surface of the stent, one on each side of the rotation centerline,
that provided relatively few instances where a jet trajectory would
not impinge on at least one stent structural element. One of these
off-axis positions was first selected to start the drug loading. A
mandrel mounted stent was positioned so that the trajectory of
jetted droplets would impinge on the stent struts at this
"off-axis" location. The motion controller was set up to move the
stent axially in the X direction and began its motion at a position
where the jet trajectory was off the end of the stent. The motion
controller ramped up to a predetermined velocity and turned on the
fluid jetting head as soon as motion along the X axis reached
constant velocity and the end of the stent struts were in a
position directly under the jet head. Every time the stent passed
completely under the jet head along this off-axis path in the X
direction, the motion controller would then ramp down the velocity,
stop and rotate the stent 5 degrees. The linear direction was
reversed and the next pass was made. After 360 degrees was reached,
(72 passes) the table was translated approximately a distance equal
to the internal diameter of the stent (1 ID) to the other off-axis
position and 72 more passes were made for an additional rotation of
360 degrees. Each stent was thus jetted twice to obtain its drug
loading.
[0130] Seven (7) stents were loaded with drug. Observation of
drug-loaded stents under a stereomicroscope indicated that no
webbing occurred between stent struts and the surfaces were
cosmetically smooth. The stents were subsequently extracted into
isobutanol for measurement of the drug obtained and the results are
shown below.
TABLE-US-00001 Stent ABT-578 (micrograms) 1 70 2 72 3 69 4 69 5 53
6 61 7 60
[0131] The average loading obtained was 65 micrograms. The
calculated capture efficiency was 84% based on the number of
counted droplets of drug dispensed.
Example 7
Loading of PC-Coated Peripheral Stents by Reagent Jetting
[0132] In a similar feasibility demonstration experiment, a fluid
jetting system manufactured by MicroFab Technologies of Plano, Tex.
was programmed to dispense 59,904 drops, approximately 3.times.
that used for the 11 mm OC stent. These peripheral vascular stents
(SFA) were 5.times.30 mm and were mounted on a larger sized
rotation fixture. The stent matrix was much more open than seen on
the OC coronary stent; however, good capture efficiency was
obtained.
TABLE-US-00002 Stent ABT-578 (micrograms) 1 187 2 176 3 185 average
183 Avg.
[0133] The jetter dispensed 211 micrograms of drug per stent,
having a capture efficiency of 86%.
Example 8
Overcoating of a Drug-Loaded Stent with Polymer
[0134] A 10 mg/ml solution of phosphorylcholine-linked methacrylate
polymer (PC) was made in isobutanol. A total of 288 passes along
the axial dimension of the stent and over 1440 degrees of rotation
under the conditions used in previous examples, produced an
overcoat at 5 micrograms per linear mm.
Example 9
Overcoating of a Drug-Loaded Stent with Polymer having a Variable
Areal Density
[0135] A 10 mg/ml solution of phosphorylcholine-linked methacrylate
polymer (PC) is made in isobutanol. The linear travel speed of the
stent under the jet head is programmed to be 50% slower during the
beginning 25% of the stent length and the ending 25% of length. The
jetting rate is not varied over the length of the stent. A total of
288 passes along the axial dimension of the stent and over 1440
degrees of rotation are made. Under these conditions, the stent
obtains an increased amount of PC on both ends of the stent
compared to the middle regions.
Example 10
Drug-Loaded Stent having a Variable Areal Density of Drug
[0136] A stock jetting solution of 20 mg/ml ABT-578+4 mg/ml
phosphorylcholine-linked methacrylate polymer (PC) in isobutanol is
prepared. The linear travel speed of the stent under the jet head
is programmed to be 50% faster during the beginning 25% of the
stent length and the ending 25% of length. The jetting rate is not
varied over the length of the stent. A total of 144 passes along
the axial dimension of the stent and over 720 degrees of rotation
are made. Under these conditions, the stent obtains a decreased
amount of ABT-578 on both ends of the stent compared to the middle
regions.
[0137] It is understood that the foregoing detailed description and
accompanying examples are merely illustrative and are not to be
taken as limitations upon the scope of the invention, which is
defined solely by the appended claims and their equivalents.
Various changes and modifications to the disclosed embodiments will
be apparent to those skilled in the art. For example, a
charge-and-deflect dispenser can be replaced with a drop-on-demand
fluid jetter, or vice versa. Such changes and modifications,
including without limitation those relating to the chemical
structures, substituents, derivatives, intermediates, syntheses,
formulations and or methods of use of the invention, can be made
without departing from the spirit and scope thereof.
* * * * *